Through co-evolution with hosts, herpesviruses have acquired strategies to exploit their hosts, allowing their own life-long persistence while intermittently being secreted and transmitted to naive hosts. By evading host defense mechanisms, herpesviruses can persist in hosts and cause various diseases. Members of the gamma-herpesvirus subfamily (Epsetin-Barr virus, Kaposi's sarcoma-associated herpesviruses and gamma herpesvirus-68) are distinct in their ability to establish latent infections in lymphocytes and cause benign or malignant tumors in infected hosts. It remains elusive how gamma-herpesviruses evade host innate immunity during their acute and persistent infections. Understanding the mechanisms of viral evasion mechanism is essential for developing approaches to prevent or control the virus associated cancers. Innate immunity is not only the first line of defense against pathogens, but is also critical for stimulating adaptive immune responses. The objective is to understand the mechanisms by which cells mount innate defense responses and tumor-associated-herpesviruses thwart components of the defense mechanisms, to establish a foundation for rational design of vaccine candidates that can elicit effective immune responses and reduce associated cancer incidence. There are four projects: 1) Interactions of gamma-herpesviruses with NLRs (Cart Ware); 2) Regulators of innate immune responses to gamma-herpesvirus infection (Sumit Chanda); 3) Role of microRNAs in regulating host interactions (Tariq Rana); 4) Restoring immune responses to gamma-herpesviruses (Ren Sun); coordinated by an Administrative Core (Ren Sun) and facilitated by a Virology Technical Service Core (Ting-Ting Wu). A team of investigators with diverse and complementing expertise has been working together and obtained critical preliminary data as the foundation for the Program. The understanding of the molecular and cellular mechanisms underlying the interactions between virus-host innate defenses will be utilized to develop a new vaccine strategy. This translational research program will provide critical information for vaccine development to prevent cancers associated with gamma-herpesviruses.